TY - JOUR
T1 - Genetic alterations of the SUMO isopeptidase SENP6 drive lymphomagenesis and genetic instability in diffuse large B-cell lymphoma
AU - Schick, Markus
AU - Zhang, Le
AU - Maurer, Sabine
AU - Maurer, Hans Carlo
AU - Isaakaidis, Konstandina
AU - Schneider, Lara
AU - Patra, Upayan
AU - Schunck, Kathrin
AU - Rohleder, Elena
AU - Hofstetter, Julia
AU - Baluapuri, Apoorva
AU - Scherger, Anna Katharina
AU - Slotta-Huspenina, Julia
AU - Hettler, Franziska
AU - Weber, Julia
AU - Engleitner, Thomas
AU - Maresch, Roman
AU - Slawska, Jolanta
AU - Lewis, Richard
AU - Istvanffy, Rouzanna
AU - Habringer, Stefan
AU - Steiger, Katja
AU - Baiker, Armin
AU - Oostendorp, Robert A.J.
AU - Miething, Cornelius
AU - Lenhof, Hans Peter
AU - Bassermann, Florian
AU - Chapuy, Björn
AU - Wirth, Matthias
AU - Wolf, Elmar
AU - Rad, Roland
AU - Müller, Stefan
AU - Keller, Ulrich
N1 - Publisher Copyright:
© 2022, The Author(s).
PY - 2022/12
Y1 - 2022/12
N2 - SUMOylation is a post-translational modification of proteins that regulates these proteins’ localization, turnover or function. Aberrant SUMOylation is frequently found in cancers but its origin remains elusive. Using a genome-wide transposon mutagenesis screen in a MYC-driven B-cell lymphoma model, we here identify the SUMO isopeptidase (or deconjugase) SENP6 as a tumor suppressor that links unrestricted SUMOylation to tumor development and progression. Notably, SENP6 is recurrently deleted in human lymphomas and SENP6 deficiency results in unrestricted SUMOylation. Mechanistically, SENP6 loss triggers release of DNA repair- and genome maintenance-associated protein complexes from chromatin thereby impairing DNA repair in response to DNA damages and ultimately promoting genomic instability. In line with this hypothesis, SENP6 deficiency drives synthetic lethality to Poly-ADP-Ribose-Polymerase (PARP) inhibition. Together, our results link SENP6 loss to defective genome maintenance and reveal the potential therapeutic application of PARP inhibitors in B-cell lymphoma.
AB - SUMOylation is a post-translational modification of proteins that regulates these proteins’ localization, turnover or function. Aberrant SUMOylation is frequently found in cancers but its origin remains elusive. Using a genome-wide transposon mutagenesis screen in a MYC-driven B-cell lymphoma model, we here identify the SUMO isopeptidase (or deconjugase) SENP6 as a tumor suppressor that links unrestricted SUMOylation to tumor development and progression. Notably, SENP6 is recurrently deleted in human lymphomas and SENP6 deficiency results in unrestricted SUMOylation. Mechanistically, SENP6 loss triggers release of DNA repair- and genome maintenance-associated protein complexes from chromatin thereby impairing DNA repair in response to DNA damages and ultimately promoting genomic instability. In line with this hypothesis, SENP6 deficiency drives synthetic lethality to Poly-ADP-Ribose-Polymerase (PARP) inhibition. Together, our results link SENP6 loss to defective genome maintenance and reveal the potential therapeutic application of PARP inhibitors in B-cell lymphoma.
UR - http://www.scopus.com/inward/record.url?scp=85122801132&partnerID=8YFLogxK
U2 - 10.1038/s41467-021-27704-8
DO - 10.1038/s41467-021-27704-8
M3 - Article
C2 - 35022408
AN - SCOPUS:85122801132
SN - 2041-1723
VL - 13
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 281
ER -